PDBsum entry 1epr

Hydrolase/hydrolase inhibitor

PDB id: 1epr

Contents

Protein chain

330 a.a. *

Ligands

0QS

Waters ×346

* Residue conservation analysis

PDB id:

1epr

Name:

Hydrolase/hydrolase inhibitor

Title:

Endothia aspartic proteinase (endothiapepsin) complexed with pd-135, 040

Structure:

Endothiapepsin. Chain: e. Engineered: yes

Source:

Cryphonectria parasitica. Chestnut blight fungus. Organism_taxid: 5116

Resolution:

2.30Å R-factor: 0.181

Authors:

M.Badasso,M.Crawford,J.B.Cooper,T.L.Blundell

Key ref:

D.Bailey and J.B.Cooper (1994). A structural comparison of 21 inhibitor complexes of the aspartic proteinase from Endothia parasitica. Protein Sci, 3, 2129-2143. PubMed id: 7703859 DOI: 10.1002/pro.5560031126

Date:

27-Jul-94 Release date: 20-Dec-94

Protein chain

P11838  (CARP_CRYPA) -  Endothiapepsin from Cryphonectria parasitica

Seq: 419 a.a.

Struc: 330 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.23.22 - endothiapepsin.
• Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1', but does not cleave 14-Ala-|-Leu-15 in the B chain of insulin or Z-Glu-Tyr. Clots milk.

DOI no: 10.1002/pro.5560031126

Protein Sci 3:2129-2143 (1994)

PubMed id: 7703859

A structural comparison of 21 inhibitor complexes of the aspartic proteinase from Endothia parasitica.

D.Bailey, J.B.Cooper.

ABSTRACT

The aspartic proteinases are an important family of enzymes associated with several pathological conditions such as hypertension (renin), gastric ulcers (pepsin), neoplastic disease (cathepsins D and E), and AIDS (HIV proteinase). Studies of inhibitor binding are therefore of great importance for design of novel inhibitors for potential therapeutic applications. Numerous X-ray analyses have shown that transition-state isostere inhibitors of aspartic proteinases bind in similar extended conformations in the active-site cleft of the target enzyme. Upon comparison of 21 endothiapepsin inhibitor complexes, the hydrogen bond lengths were found to be shortest where the isostere (P1-P'1) interacts with the enzyme's catalytic aspartate pair. Hydrogen bonds with good geometry also occur at P'2, and more so at P3, where a conserved water molecule is involved in the interactions. Weaker interactions also occur at P2, where the side-chain conformations of the inhibitors appear to be more variable than at the more tightly held positions. At P2 and, to a lesser extent, P3, the side-chain conformations depend intriguingly on interactions with spatially adjacent side chains, namely P'1 and P1, respectively. The tight binding at P1-P'1, P3, and P'2 is also reflected in the larger number of van der Waals contacts and the large decreases in solvent-accessible area at these positions, as well as their low temperature factors. Our analysis substantiates earlier proposals for the locations of protons in the transition-state complex. Aspartate 32 is probably ionized in the complexes, its charge being stabilized by 1, or sometimes 2, hydrogen bonds from the transition-state analogues at P1. The detailed comparison also indicates that the P1 and P2 residues of substrate in the ES complex may be strained by the extensive binding interactions at P3, P'1, and P'2 in a manner that would facilitate hydrolysis of the scissile peptide bond.

Selected figure(s)

Figure 3.
Fig. 3. hydrogen bondinteractions with inhibitorsare shown (top) with agraph showing te donor-acceptor dis- tances for the 21 nhibitor complexes (+ indicates an 0. . .H-N interaction, @ indicates an 0. . .H-N nteraction with an at theproton greater than 160'. and X indicates n 0. . .H-0 interaction). Some of theiteractions with the aspartate carbox- yls willbe van er Waals contactsratherthan hydrogen bonds (see text for discussion of proton locations).

Figure 5.
Fig. 5. A: distribution of x, angles observed for each position of the inhibitors. The distribution of x2 angles.

The above figures are reprinted by permission from the Protein Society: Protein Sci (1994, 3, 2129-2143) copyright 1994.

Figures were selected by an automated process.